1. Field of the Invention
The invention relates to a novel series of 13,14-dihydro-15-alkenyl prostaglandins and 13,14-dihydro-15-alkynyl prostaglandins, certain analogs, esters thereof and novel intermediates for their preparation. In particular, it relates to novel 9-oxo-11.alpha.,15-dihydroxyprosta-5,16-dienoic acids, 9-oxo-11.alpha.,15-dihydroxyprosta-5-ene-16-yneoic acids, certain analogs and esters thereof which possess selective bronchodilator activity; and various novel intermediates useful in their preparation. The 17-phenyl-.omega.-trinorprostaglandins of this series also possess useful antisecretory activity.
2. Description of the Prior Art
The prostaglandins are C-20 unsaturated fatty acids which exhibit diverse physiological effects. Each of the known naturally occurring prostaglandins is derived from prostanoic acid which has the structure and position numbering: ##STR1## [Bergstrom et al., Pharmacol. Rev., 20, 1 (1968), and references cited therein] A systematic name for prostanoic acid is 7-[(2.beta.-octyl)-cyclopent-1.alpha.-yl]heptanoic acid.
PGE.sub.2 has the structure: ##STR2##
PGF.sub.2.alpha. has the structure: ##STR3##
PGF.sub.2.beta. has the structure ##STR4##
PGA.sub.2 is 11-desoxy-PGE.sub.2 with a double bond in the 5-membered ring between carbons 10 and 11.
PGB.sub.2 is identical to PGA.sub.2, except that the double bond is shifted to the 8,12-position.
Each of the PG.sub.1 prostaglandins, PGE.sub.1, PGF.sub.1.alpha., PGF.sub.1.beta., PGA.sub.1 and PGB.sub.1, has a structure the same as the corresponding PG.sub.2 compound except that the cis double bond between C-5 and C-6 is replaced by a single bond.
Broken line attachments to the cyclopentane ring indicate substituents in alpha configuration, i.e., below the plane of the cyclopentane ring. Solid line attachments to the cyclopentane ring indicate substituents in beta configuration, i.e., above the plane of the cyclopentane ring.
The side-chain hydroxy at C-15 in the above formulas is in S configuration. [See Nature, 212, 38 (1966) for discussion of the stereochemistry of the prostaglandins]
The various physiological effects of the prostaglandins are reviewed in "The Prostaglandins, Progress in Research," Wiley-Interscience Division of John Wiley and Sons, Inc., New York, N. Y., 1972, M. M. Karim, editor. For instance, the prostaglandins of the E and A series are potent vasidilators (Bergstrom, et al., Acta. Physiol. Scand., 64: 332-333, 1965 and Bergstrom, et al., Life Sci., 6: 449-455, 1967) and lower systemic arterial blood pressure (vasodepression) on intravenous administration (Weeks and King, Federation Proc. 23: 327, 1964; Bergstrom, et al., 1965, op. cit.; Carlson, et al., Acta. Med. Scand., 183: 423-430, 1968; and Carlson, et al., Acta. Physiol. Scand., 75: 161-169, 1969). Another well known physiological action for PGE.sub.1 and PGE.sub.2 is as a bronchodilator (Cuthbert, Brit. Med. J., 4: 723-726, 1969).
Another important physiological role for the natural prostaglandins is in connection with the reproductive cycle. PGE.sub.2 is known to possess the ability to induce labor (Karim, et al., J. Obstet. Gynaec. Brit. Cwlth., 77: 200-210, 1970) and also to induce therapeutic abortion (Bygdeman, et al., Contraception, 4: 293, 1971) and to be useful for control of fertility (Karim, Contraception, 3: 1973, 1971). Patents have been obtained for several prostaglandins of the E and F series as inducers of labor in mammals (Belgian Pat. No. 754,158 and West German Pat. No. 2,034,641), and on PGF.sub.1, F.sub.2, and F.sub.3 for control of the reproductive cycle (South African Pat. No. 69/6089).
Still other known physiological activities for PGE.sub.1 are in the inhibition of gastric acid secretion (Shaw and Ramwell, in: Worcester Symp. on Prostaglandins, New York, Wiley, 1968, pages 55-64) and also of platelet aggregation (Emmons, et al., Brit. Med. J., 2: 468-472, 1967).
Very small doses of PGE.sub.1 and PGE.sub.2 have been found to cause diarrhea in animals including humans (Bennett, in The Prostaglandins, Progress in Research, Wiley-Interscience Division of John Wiley and Sons, Inc., New York, N. Y., 1972, M. M. Karim, editor, pages 212-214).
Use of the natural prostaglandins as bronchodilators is complicated by the above-mentioned diversity of activity.
The synthesis of the novel compounds of the invention employs 2-[5.alpha.-hydroxy-3.alpha.-(tetrahydropyran-2-yloxy)-2.beta.-aldehydocyc lopent-1.alpha.-yl]acetic acid, .gamma.-lactone [Corey, et al., J. Amer. Chem. Soc., 93, 1490 (1971)] as starting material.